Despite the presence of HIV-1 in the oral cavity, transmission of the virus through saliva has not been proven. The rarity of oral transmission of HIV-1 by saliva, despite identification of HIV-1 by in situ hybridization in more than 30% of the salivary glands evaluated from AIDS patients and demonstration of HIV-1 in oral secretions, implicates a key role for innate antiviral activity in suppressing transmission. One such endogenous antiviral molecule, secretory leukocyte protease inhibitor (SLPI), inhibits HIV-1 infection of mononuclear cells during or soon after internalization. To further clarify the function of SLPI in innate host defense, efforts are underway to generate mice homozygous for a null mutation of SLPI. In additional studies focusing on the regulation of HIV production after infection, opportunistic pathogens were shown to influence viral replication. By in situ hybridization, unprecedented levels of HIV were detected in co-infected tissues. Striking concentrations of HIV-1 RNA signal were evident within P.carinii or M.avium infected lymph nodes, and the majority of HIV-positive cells expressed macrophage-specific markers. Staining for acid fast organisms together with in situ hybridization revealed co-localization of HIV and M.avium in mononuclear and multinucleated Langhans' cells. Preliminary evidence favors aberrant macrophage cytokine expression as a potential mechanism controlling this massive viral replication, even in the near absence of CD4+ lymphocytes. These novel observations on the dynamic relationship between opportunistic pathogens, macrophages and high levels of viral replication suggest that co-infection is an impetus for HIV production, and that macrophages contribute to plasma viremia, particularly in late-stage HIV-disease. Importantly, these observations suggest that OI therapy may not only diminish the opportunistic pathogens, but also decrease viral burden.